Ingenol-3-angelate (PEP005, ingenol mebutate, Picato®) is a diterpene-ester of the ingenol family which is isolated from various Euphorbia species, particularly from Euphorbia peplus. Picato® is marketed for treatment of actinic keratosis and is presently subject for clinical development for the treatment of non-melanoma skin cancer.
Ingenol-3-angelate is believed to have a dual mode of action: 1) Induction of cell death by direct cytoxicity or induction of apoptosis and 2) an immunostimulatory effect dominated by neutrophil recruitment and activation (Rosen, R. H., et al., J Am Acad Dermatol (2012); 66:486-93; Ersvaer, E., et al., Toxins, (2010), 2, 174-194). Nanomolar concentrations of the agent cause activation and modulation of protein kinase C (PKC) classical and novel isoforms, with particular importance of PKCdelta. Through activation of PKCdelta the agent induces apoptosis in susceptible cells (Hampson, P., et al., Blood, (2005), 106, 1362-1368; Cozzi, S. J., et al., Cancer Res, (2006), 66, 10083-10091). Rapid cytotoxicity on cancer cells is observed at high micromolar concentrations (Ogbourne, S. M., et al., Cancer Res (2004), 64, 2833-2839). Through activation of various PKC isoforms the agent also induces pro-inflammatory effects, including release of pro-inflammatory mediators (Challacombe, J. M., et al., J Immunol (2006), 177, 8123-8132); activation of vascular endothelium (Hampson, P., et al., Cancer Immunol Immunother, (2008), 57, 1241-1251); chemoattraction of neutrophils through induction of interleukin 8 in keratinocytes and development of specific anti-cancer immune responses by CD8+ cells through adjuvant properties in animal models (Le, T. T., et al., Vaccine, (2009), 27, 3053-3062).
Compounds exerting dual mode of action by induction of cell death by direct cytoxicity or induction of apoptosis, and by an immunostimulatory effect involving neutrophil recruitment and activation, may be useful for treatment of conditions associated with hyperplasia or neoplasia. Compounds inducing cell death by primary and/or secondary necrosis and compounds exhibiting a pro-apoptotic effect may reduce unwanted cell growth and remove unwanted cells, and furthermore, stimulation of the innate immune response and adjuvant effects may augment the biological response against aberrant or transformed cells.
WO2012083954 disclose carbocyclic 3-O-acyl ingenol derivatives.
Marco, J. A. et. al.; Phytochemistry, (1997) 45, 563-70; and Evans, F. J.; Phytochemical Reports, (1974), 13, 2324-25, disclose 5-deoxy-ingenol derivatives.
Upadhyay, R. R. et. al; Curr. Science (1987), 56, 1058-1059 disclose 4-deoxy-ingenol derivatives.
There is a need to find new ingenol derivatives which induce cell death by cytotoxicity or apoptosis and/or induce an immunostimulatory effect.

The present invention discloses a method of preparing 3-O-acyl ingenol analogues wherein the substituents at C-4, C-5 and C-11 of the ingenol skeleton have been modified.
Synthetic routes leading to such analogues have not previously been disclosed.
It has surprisingly been found that carbocyclic 3-O-acyl ingenol analogues wherein the ingenol skeleton has been modified at the C-4, C-5 and C-11 positions exhibit properties which make them useful for treatment of conditions associated with the use of ingenol-3-angelate or useful for conditions which are affected by induction of cell death by cytoxicity or induction of apoptosis and/or by an immunostimulatory effect.
Compounds of the present invention stimulate neutrophil oxidative burst, which is part of the innate immune response.
Compounds of the present invention stimulate keratinocyte IL-8 release, thus inducing an immunostimulatory effect.
Compounds of the present invention are PKCδ activators.
Compounds of the present invention are PKCβ activators
Some compounds of the present invention may induce rapid necrosis.